The dynamics of spreading depolarizations (SD) operate at both the single cell and network level. As single cells bifurcate into extreme regions of their state space, network effects are all that remain to hold back the forthcoming wave of depolarization. Therefore, we investigated excitatory/inhibitory network effects near the leading edge of spreading depolarizations. We imaged >1000 layer 2/3 pyramidal neurons in vivo with GCaMP6f in awake mice before, during and after spreading depolarizations. We observed a leading edge of inhibition in front of the depolarization wave. The inhibition was inferred from decreased iCa levels and decreased calcium spikes. We hypothesize that inhibitory interneurons with dendritic arbors near the extracellular potassium gradient are strongly inhibiting pyramidal neurons in an apparent failed attempt to stop the wave. SDs are incredibly metabolically expensive and likely damaging in the context of stroke. Therefore, understanding the mechanisms that attempt to limit SDs and their failure could lead to therapeutic targets.